PKM2 modulators for use in the treatment of cancer

ABSTRACT

Compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of cancer.

CLAIM OF PRIORITY

The present application is a continuation of International ApplicationNo. PCT/US2010/033610, filed May 4, 2010, published as InternationalPublication No. WO 2010/129596 on Nov. 11, 2010, which claims priorityfrom U.S. Ser. No. 61/175,217, filed May 4, 2009, each of which isincorporated herein by reference in its entirety.

BACKGROUND OF INVENTION

Cancer cells rely primarily on glycolysis to generate cellular energyand biochemical intermediates for biosynthesis of lipids andnucleotides, while the majority of “normal” cells in adult tissuesutilize aerobic respiration. This fundamental difference in cellularmetabolism between cancer cells and normal cells, termed the WarburgEffect, has been exploited for diagnostic purposes, but has not yet beenexploited for therapeutic benefit.

Pyruvate kinase (PK) is a metabolic enzyme that convertsphosphoenolpyruvate to pyruvate during glycolysis. Four PK isoformsexist in mammals: the L and R isoforms are expressed in liver and redblood cells, the M1 isoform is expressed in most adult tissues, and theM2 isoform is a splice variant of M1 expressed during embryonicdevelopment. All tumor cells exclusively express the embryonic M2isoform. A well-known difference between the M1 and M2 isoforms of PK isthat M2 is a low-activity enzyme that relies on allosteric activation bythe upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP),whereas M1 is a constitutively active enzyme.

All tumor cells exclusively express the embryonic M2 isoform of pyruvatekinase, suggesting PKM2 as a potential target for cancer therapy. PKM2is also expressed in adipose tissue and activated T-cells. Thus, themodulation (e.g., inhibition or activation) of PKM2 may be effective inthe treatment of, e.g., obesity, diabetes, autoimmune conditions, andproliferation-dependent diseases, e.g., benign prostatic hyperplasia(BPH). Current modulators (e.g., inhibitors) of pyruvate kinase are notselective, making it difficult to treat disease related to pyruvatekinase function.

Furthermore, phosphotyrosine peptide binding to PKM2 leads to adissociation of FBP from PKM2 and conformational changes of PKM2 from anactive, tetrameric form to an inactive form. Compounds that bind to PKM2and lock the enzyme in the active confirmation will lead to the loss ofallosteric control of PKM2 needed for shunting biochemical intermediatesfrom glycolysis into biosynthesis of nucleotides and lipids. Thus, theactivation of PKM2 can also inhibit the growth and proliferation ofcancer cells, activated immune cells, and fat cells.

There is a continuing need for novel treatments of diseases such ascancer, diabetes, obesity, autoimmune conditions,proliferation-dependent diseases (e.g., BPH), and other diseases relatedto the function of pyruvate kinase (e.g., PKM2).

SUMMARY OF INVENTION

Described herein are compounds that modulate pyruvate kinase M2 (PKM2)and pharmaceutically acceptable salts, solvates, and hydrates thereof.For example, a compound described herein may activate or inhibit PKM2.This invention also provides compositions and pharmaceutical kitscomprising a compound of this invention and the use of such compositionsand kits in methods of treating diseases and conditions that are relatedto pyruvate kinase function (e.g., PKM2 function), including, e.g.,cancer, diabetes, obesity, autoimmune disorders, and benign prostatichyperplasia (BPH).

In one aspect, the invention features a compound of formula (I):

wherein:

m is an integer from 0 to 5;

each R¹ is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁₋₆ haloalkoxy, halo, acetyl, —NO₂, aryl, aralkyl,heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl, —C(O)-aralkyl, —C(O)—C₁₋₆alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl, aralkyl and heteroarylgroup is optionally substituted with 0-3 occurrences of R^(c) andwherein two R¹ groups taken together with the carbon atoms to which theyare attached form a heterocyclyl ring;

n is an integer from 1 to 3;

each R² is independently selected from C₁-C₆ alkyl and halo;

B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C₁₋₆aralkyl, or C₁₋₆ heteroaralkyl;

L is a linker selected from —SO₂—, —SO₂NR^(a)— and —NR^(a)SO₂—;

each R^(a) is independently selected from hydrogen and C₁-C₆ alkyl;

X and Y are each independently selected from O, S, NR^(b) and CH₂,wherein at least one of X and Y is O or S;

Z is O or S;

each R^(b) is independently selected from hydrogen, C₁₋₆ aralkyl, andC₁-C₆ alkyl substituted with 0-1 occurrences of R^(c); and

R^(c) is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, NR^(d)R^(d), and heterocyclyl and wherein two R^(c)groups taken together with the carbon atoms to which they are attachedform a heterocyclyl ring; and

R^(d) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, each R¹ is independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, halo, acetyl and —NO₂;

In some embodiments, each R^(b) is independently selected from hydrogenand C₁-C₆ alkyl.

In some embodiments, B is a monocyclic heteroaryl, cycloalkyl,heterocyclyl, C₁₋₆ aralkyl, or C₁₋₆ heteroaralkyl.

In some embodiments, B is a monocyclic heterocyclyl (e.g., a 6-memberedmonocyclic heterocyclyl). In some embodiments, B is a 6-memberednitrogen containing monocyclic heterocyclyl (e.g., piperazinyl). In someembodiments, B is unsubstituted piperazinyl. In some embodiments, B ispiperazinyl substituted with an R¹. In some embodiments, B is a7-membered nitrogen containing monocyclic heterocyclyl (e.g.,1,4-diazepam). In some embodiments, B is unsubstituted 1,4-diazepam. Insome embodiments, B is 1,4-diazepam substituted with an R¹.

In some embodiments, B is a monocyclic heteroaryl. In some embodiments,B is a 5-membered monocyclic heteroaryl (e.g., thiophenyl). In someembodiments, B is a 6-membered monocyclic heteroaryl, e.g., a 6-memberednitrogen-containing monocyclic heteroaryl (e.g., pyridyl). In someembodiments, B is pyridyl substituted with 2 R¹. In some embodiments,one R¹ is halo and the other is haloalkyl. In some embodiments, one R¹is chloro and the other is trifluoromethyl.

In some embodiments, B is monocyclic aryl (e.g., phenyl). In someembodiments, B is unsubstituted phenyl. In some embodiments, B is phenylsubstituted with one R¹. In some embodiments, B is phenyl substitutedwith two R¹.

In some embodiments, n is 1. In some embodiments, R² is C₁-C₆ alkyl(e.g., methyl). In some embodiments, R² is halo (e.g., fluoro, chloro orbromo).

In some embodiments, L is a linker selected from —SO₂—. In someembodiments, L is a linker selected from —SO₂NR^(a)— and —NR^(a)SO₂—. Insome embodiments, L is —SO₂NR^(a)—. In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., methyl, ethylor isopropyl). In some embodiments, L is —NR^(a)SO₂—. In someembodiments, R^(a) is hydrogen. In some embodiments, R^(a) is C₁-C₆alkyl (e.g., methyl, ethyl or isopropyl).

In some embodiments, X is S. In some embodiments, X is O. In someembodiments, X is NR^(b). In some embodiments, R^(b) is hydrogen. Insome embodiments, R^(b) is C₁-C₆ alkyl (e.g., methyl, ethyl, isopropylor sec-butyl). In some embodiments, Y is S. In some embodiments, Y is O.In some embodiments, Y is NR^(b). In some embodiments, R^(b) ishydrogen. In some embodiments, R^(b) is C₁-C₆ alkyl (e.g., methyl,ethyl, isopropyl or sec-butyl).

In some embodiments, one of X and Y is O and the other is S. In someembodiments, one of X and Y is O and the other is NR^(b). In someembodiments, R^(b) is hydrogen. In some embodiments, R^(b) is C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl or sec-butyl). In someembodiments, one of X and Y is S and the other is NR^(b). In someembodiments, R^(b) is hydrogen. In some embodiments, R^(b) is C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl or sec-butyl).

In some embodiments, Z is O.

In some embodiments, the compound of formula (I) is represented by thefollowing formula:

In one aspect, the invention features a compound of formula (II):

wherein:

m is an integer from 0 to 5;

each R¹ is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁₋₆ haloalkoxy, halo, acetyl, —NO₂, aryl, aralkyl,heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl, —C(O)-aralkyl, —C(O)—C₁₋₆alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl, aralkyl and heteroarylgroup is optionally substituted with 0-3 occurrences of R^(c) andwherein two R¹ groups taken together with the carbon atoms to which theyare attached form a heterocyclyl ring;

n is an integer from 1 to 3;

each R² is independently selected from C₁-C₆ alkyl and halo;

B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C₁₋₆aralkyl, or C₁₋₆ heteroaralkyl;

L is a linker selected from —SO₂—, —SO₂NR^(a)— and —NR^(a)SO₂—;

each R^(a) is independently selected from hydrogen and C₁-C₆ alkyl;

Z is O or S;

each R^(b) is independently selected from hydrogen, C₁₋₆ aralkyl, andC₁-C₆ alkyl substituted with 0-1 occurrences of R^(c); and

R^(c) is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, NR^(d)R^(d), and heterocyclyl and wherein two R^(c)groups taken together with the carbon atoms to which they are attachedform a heterocyclyl ring; and

R^(d) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, each R¹ is independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, halo, acetyl and —NO₂.

In some embodiments, L is a linker selected from —SO₂NR^(a)— and—NR^(a)SO₂—.

In some embodiments, each R^(b) is independently selected from hydrogenand C₁-C₆ alkyl.

In some embodiments, B is a monocyclic heteroaryl, cycloalkyl,heterocyclyl, C₁₋₆ aralkyl, or C₁₋₆ heteroaralkyl.

In some embodiments, B is a monocyclic heterocyclyl (e.g., a 6-memberedmonocyclic heterocyclyl). In some embodiments, B is a 6-memberednitrogen containing monocyclic heterocyclyl (e.g., piperazinyl). In someembodiments, B is unsubstituted piperazinyl. In some embodiments, B ispiperazinyl substituted with an R¹. In some embodiments, B is a7-membered nitrogen containing monocyclic heterocyclyl (e.g.,1,4-diazepam). In some embodiments, B is unsubstituted 1,4-diazepam. Insome embodiments, B is 1,4-diazepam substituted with an R¹.

In some embodiments, B is a monocyclic heteroaryl. In some embodiments,B is a 5-membered monocyclic heteroaryl (e.g., thiophenyl). In someembodiments, B is a 6-membered monocyclic heteroaryl, e.g., a 6-memberednitrogen-containing monocyclic heteroaryl (e.g., pyridyl). In someembodiments, B is pyridyl substituted with 2 R¹. In some embodiments,one R¹ is halo and the other is haloalkyl. In some embodiments, one R¹is chloro and the other is trifluoromethyl.

In some embodiments, B is monocyclic aryl (e.g., phenyl). In someembodiments, B is unsubstituted phenyl. In some embodiments, B is phenylsubstituted with one R¹. In some embodiments, R¹ is halo (e.g., fluoro,chloro or bromo). In some embodiments, R¹ is C₁-C₆ alkyl (e.g., methyl).In some embodiments, R¹ is C₁-C₆ alkoxy (e.g., methoxy). In someembodiments, R¹ is acetyl. In some embodiments, R¹ is —NO₂.

In some embodiments, B is phenyl substituted with two R¹. In someembodiments, one R¹ is halo (e.g., fluoro or chloro) and the other isC₁-C₆ alkoxy (e.g., methoxy).

In some embodiments, both R¹ are halo (e.g., fluoro or chloro). In someembodiments, one R¹ is C₁-C₆ alkyl (e.g., methyl) and the other is C₁-C₆alkoxy (e.g., methoxy). In some embodiments, both R¹ are C₁-C₆ alkoxy(e.g., methoxy).

In some embodiments, B is a 5-membered monocyclic heteroaryl (e.g.,thiophenyl). In some embodiments, B is a 6-membered monocyclicheteroaryl, e.g., a 6-membered nitrogen-containing monocyclic heteroaryl(e.g., pyridyl). In some embodiments, B is pyridyl substituted with 2R¹. In some embodiments, one R¹ is halo and the other is haloalkyl. Insome embodiments, one R¹ is chloro and the other is trifluoromethyl. Insome embodiments, B is cycloalkyl (e.g., cyclohexyl).

In some embodiments, n is 1. In some embodiments, R² is C₁-C₆ alkyl(e.g., methyl). In some embodiments, R² is halo (e.g., fluoro, chloro orbromo).

In some embodiments, L is —SO₂—. In some embodiments, L is —SO₂NR^(a)—.In some embodiments, R^(a) is hydrogen. In some embodiments, R^(a) isC₁-C₆ alkyl (e.g., methyl, ethyl or isopropyl). In some embodiments, Lis —NR^(a)SO₂—. In some embodiments, R^(a) is hydrogen. In someembodiments, R^(a) is C₁-C₆ alkyl (e.g., methyl, ethyl or isopropyl).

In some embodiments, Z is O.

In some embodiments, the compound of formula (II) is represented by thefollowing formula:

In one aspect, the invention features a compound of formula (III):

wherein:

m is an integer from 0 to 5;

each R¹ is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁₋₆ haloalkoxy, halo, acetyl, —NO₂, aryl, aralkyl,heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl, —C(O)-aralkyl, —C(O)—C₁₋₆alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl, aralkyl and heteroarylgroup is optionally substituted with 0-3 occurrences of R^(c) andwherein two R¹ groups taken together with the carbon atoms to which theyare attached form a heterocyclyl ring;

each R² is independently selected from C₁-C₆ alkyl and halo;

each R^(b) is independently selected from hydrogen, C₁₋₆ aralkyl, andC₁-C₆ alkyl substituted with 0-1 occurrences of R^(c);

R^(c) is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, NR^(d)R^(d), and heterocyclyl and wherein two R^(c)groups taken together with the carbon atoms to which they are attachedform a heterocyclyl ring; and

R^(d) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, each R¹ is independently selected from C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, halo, acetyl and —NO₂.

In some embodiments, each R² is independently C₁-C₆ alkyl.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, R¹ is halo (e.g., fluoro, chloro or bromo). In someembodiments, R¹ is C₁-C₆ alkyl (e.g., methyl). In some embodiments, R¹is C₁-C₆ alkoxy (e.g., methoxy). In some embodiments, R¹ is acetyl. Insome embodiments, R¹ is —NO₂.

In some embodiments, m is 2. In some embodiments, one R¹ is halo (e.g.,fluoro or chloro) and the other is C₁-C₆ alkoxy (e.g., methoxy). In someembodiments, both R¹ are halo (e.g., fluoro or chloro). In someembodiments, one R¹ is C₁-C₆ alkyl (e.g., methyl) and the other is C₁-C₆alkoxy (e.g., methoxy). In some embodiments, both R¹ are C₁-C₆ alkoxy(e.g., methoxy). In some embodiments, both R¹ are C₁₋₆ alkyl (e.g.,methyl).

In some embodiments, R² is methyl.

In one aspect, the invention features a pharmaceutical compositioncomprising a compound of formula (IV):

wherein:

m is an integer from 0 to 5;

each R¹ is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁₋₆ haloalkoxy, halo, acetyl, —NO₂, aryl, aralkyl,heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl, —C(O)-aralkyl, —C(O)—C₁₋₆alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl, aralkyl and heteroarylgroup is optionally substituted with 0-3 occurrences of R^(c) andwherein two R¹ groups taken together with the carbon atoms to which theyare attached form a heterocyclyl ring;

n is an integer from 0 to 3;

each R² is independently selected from C₁-C₆ alkyl and halo;

B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C₁₋₆aralkyl, or C₁₋₆ heteroaralkyl;

L is a linker selected from —SO₂—, —SO₂NR^(a)— and —NR^(a)SO₂—;

each R^(a) is independently selected from hydrogen and C₁-C₆ alkyl;

X and Y are each independently selected from O, S, NR^(b) and CH₂;

Z is O or S;

each R^(b) is independently selected from hydrogen, C₁₋₆ aralkyl, andC₁-C₆ alkyl substituted with 0-1 occurrences of R^(c); and

R^(c) is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, NR^(d)R^(d), and heterocyclyl and wherein two R^(c)groups taken together with the carbon atoms to which they are attachedform a heterocyclyl ring; and

R^(d) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, B is monocyclic aryl (e.g., phenyl). In someembodiments, B is unsubstituted phenyl. In some embodiments, B is phenylsubstituted with 1 R¹. In some embodiments, R¹ is halo (e.g., fluoro,chloro or bromo). In some embodiments, R¹ is C₁-C₆ alkyl (e.g., methylor ethyl). In some embodiments, R¹ is C₁-C₆ alkoxy (e.g., methoxy). Insome embodiments, R¹ is haloalkyl (e.g., trifluoromethyl). In someembodiments, R¹ is acetyl. In some embodiments, R¹ is —NR^(b)-acetyl(e.g., acetamide). In some embodiments, R¹ is —NO₂. In some embodiments,R¹ is —NR^(b)—SO₂-aryl (e.g., —NR^(b)—SO₂-phenyl). In some embodiments,R^(b) is H. In some embodiments, R¹ is —NH—SO₂-phenyl substituted withtwo occurrences of R^(c). In some embodiments, one R^(c) is C₁₋₆ alkoxy(e.g., methoxy) and one R^(c) is halo (e.g., fluoro or chloro). In someembodiments, both R^(c) are halo (e.g., fluoro or chloro). In someembodiments, one R^(c) is C₁₋₆ alkoxy (e.g., methoxy) and one R^(c) isC₁₋₆ alkyl (e.g., methyl).

In some embodiments, B is phenyl substituted with two R¹. In someembodiments, one R¹ is halo (e.g., fluoro or chloro) and the other isC₁-C₆ alkoxy (e.g., methoxy). In some embodiments, both R¹ are halo(e.g., fluoro or chloro). In some embodiments, one R¹ is halo (e.g.,fluoro or chloro) and one R¹ is haloalkyl (e.g., trifluoromethyl). Insome embodiments, one R¹ is halo (e.g., fluoro or chloro) and one R¹ isC₁₋₆ alkyl (e.g., methyl or ethyl). In some embodiments, one R¹ is C₁-C₆alkyl (e.g., methyl) and the other is C₁-C₆ alkoxy (e.g., methoxy). Insome embodiments, both R¹ are C₁-C₆ alkyl (e.g., methyl). In someembodiments, both R¹ are C₁-C₆ alkoxy (e.g., methoxy). In someembodiments, two R¹ groups taken together with the carbon atoms to whichthey are attached form a heterocyclyl ring. In some embodiments, two R¹groups taken together with the carbon atoms to which they are attachedform the following compound:

In some embodiments, two R¹ groups taken together with the carbon atomsto which they are attached form the following compound:

In some embodiments, B is bicyclic aryl (e.g., naphthyl). In someembodiments, B is unsubstituted naphthyl.

In some embodiments, B is monocyclic heteroaryl, e.g., a 5-memberedmonocyclic heteroaryl (e.g., thiophenyl). In some embodiments, B is a6-membered monocyclic heteroaryl, e.g., a 6-membered nitrogen-containingmonocyclic heteroaryl (e.g., pyridyl). In some embodiments, B isunsubstituted pyridyl. In some embodiments, B is pyridyl substitutedwith two R¹. In some embodiments, one R¹ is halo (e.g., chloro) and theother is haloalkyl (e.g., trifluoromethyl).

In some embodiments, B is bicyclic heteroaryl, e.g., a 10-memberedbicyclic heteroaryl (e.g., a 10-membered nitrogen containing bicyclicheteroaryl). In some embodiments, B is a 10-membered nitrogen containingbicyclic heteroaryl (e.g., quinolyl). In some embodiments, B isunsubstituted quinolyl.

In some embodiments, B is a monocyclic heterocyclyl (e.g., a 6-memberedmonocyclic heterocyclyl). In some embodiments, B is a 6-memberednitrogen containing monocyclic heterocyclyl (e.g., piperazinyl). In someembodiments, B is unsubstituted piperazinyl. In some embodiments, B ispiperazinyl substituted with an R¹. In some embodiments, R¹ is —SO₂-aryl(e.g., phenyl or naphthyl). In some embodiments, R¹ is —SO₂-phenylsubstituted with 0 occurrences of R^(c). In some embodiments, R¹ is—SO₂-naphthyl. In some embodiments, R¹ is —SO₂-phenyl substituted with 1occurrence of R^(c). In some embodiments, R^(c) is C₁₋₆ alkoxy (e.g.,methoxy). In some embodiments, R^(c) is halo (e.g., fluoro or chloro).

In some embodiments, R¹ is —SO₂-phenyl substituted with 2 occurrences ofR^(c). In some embodiments, one R^(c) is C₁₋₆ alkoxy (e.g., methoxy) andthe other R^(c) is halo (e.g., chloro or fluoro). In some embodiments,both R^(c) are halo (e.g., fluoro or chloro). In some embodiments, bothR^(c) taken together form a heterocyclyl. In some embodiments, bothR^(c) are taken together to form the compound represented below:

In some embodiments, R¹ is aralkyl (e.g., benzyl).

In some embodiments, R¹ is —C(O)—C₁₋₆ alkoxy (e.g., —C(O)-t-butoxy).

In some embodiments, R¹ is —SO₂-heteroaryl (e.g., —SO₂-pyridyl). In someembodiments, R¹ is —SO₂-pyridyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —SO₂-pyridyl substituted with 1 occurrence ofR^(c). In some embodiments, R^(c) is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R¹ is —C(O)-aralkyl (e.g., —C(O)-benzyl). In someembodiments, R¹ is —C(O)-benzyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —C(O)-benzyl substituted with 1 occurrence ofR^(c). In some embodiments, R^(c) is haloalkyl (e.g., trifluoromethyl).

In some embodiments, B is a monocyclic heterocyclyl (e.g., a 7-memberedmonocyclic heterocyclyl). In some embodiments, B is a 7-memberednitrogen containing monocyclic heterocyclyl (e.g., 1,4-diazepanyl). Insome embodiments, B is unsubstituted 1,4-diazepanyl. In someembodiments, B is 1,4-diazepanyl substituted with an R¹. In someembodiments, R¹ is —SO₂-aryl (e.g., phenyl or naphthyl). In someembodiments, R¹ is —SO₂-phenyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —SO₂-naphthyl. In some embodiments, R¹ is—SO₂-phenyl substituted with 1 occurrence of R^(c). In some embodiments,R^(c) is C₁₋₆ alkoxy (e.g., methoxy). In some embodiments, R^(c) is halo(e.g., fluoro or chloro).

In some embodiments, R¹ is phenyl substituted with 2 occurrences ofR^(c). In some embodiments, one R^(c) is C₁₋₆ alkoxy (e.g., methoxy) andthe other R^(c) is halo (e.g., chloro or fluoro). In some embodiments,both R^(c) are halo (e.g., fluoro or chloro). In some embodiments, bothR^(c) taken together form a heterocyclyl. In some embodiments, bothR^(c) are taken together to form the compound represented below:

In some embodiments, R¹ is aralkyl (e.g., benzyl).

In some embodiments, R¹ is —C(O)—C₁₋₆ alkoxy (e.g., —C(O)-t-butoxy).

In some embodiments, R¹ is —SO₂-heteroaryl (e.g., —SO₂-pyridyl). In someembodiments, R¹ is —SO₂-pyridyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —SO₂-pyridyl substituted with 1 occurrence ofR^(c). In some embodiments, R^(c) is haloalkyl (e.g., trifluoromethyl).

In some embodiments, In some embodiments, B is a monocyclic heterocyclyl(e.g., a 6-membered monocyclic heterocyclyl). In some embodiments, B isa 6-membered nitrogen containing monocyclic heterocyclyl (e.g.,piperidinyl). In some embodiments, B is unsubstituted piperidinyl. Insome embodiments, B is piperidinyl substituted with an R¹. In someembodiments, R¹ is —C(O)—NR^(b)-aryl (e.g., —C(O)—NR^(b)-phenyl. In someembodiments, R^(b) is H. In some embodiments, R¹ is —C(O)—NH-phenylsubstituted with two occurrences of R^(c). In some embodiments, bothR^(c) are C₁₋₆ alkyl (e.g., methyl).

In some embodiments, B is cycloalkyl (e.g., cyclohexyl).

In some embodiments, B is C₁₋₆ aralkyl (e.g., benzyl). In someembodiments, B is benzyl substituted with 0 occurrences of R¹.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, R² is C₁-C₆ alkyl (e.g., methyl). In some embodiments, R²is halo (e.g., fluoro, chloro or bromo).

In some embodiments, L is —SO₂NR^(a)—. In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., methyl, ethylor isopropyl). In some embodiments, L is —NR^(a)SO₂—. In someembodiments, R^(a) is hydrogen. In some embodiments, R^(a) is C₁-C₆alkyl (e.g., methyl, ethyl or isopropyl).

In some embodiments, X is S. In some embodiments, X is O. In someembodiments, X is NR^(b). In some embodiments, R^(b) is hydrogen. Insome embodiments, R^(b) is C₁-C₆ alkyl substituted with 0 occurrences ofR^(c) (e.g., methyl, ethyl, isopropyl or sec-butyl). In someembodiments, R^(b) is aralkyl (e.g., benzyl or phenethyl). In someembodiments, R^(b) is C₁₋₆ alkyl substituted with 1 occurrence of R^(c)(e.g., methyl, ethyl or propyl). In some embodiments, R^(c) is C₁₋₆alkoxy (e.g., methoxy). In some embodiments, R^(c) is heterocyclyl(e.g., morpholinyl or piperidinyl). In some embodiments, R^(c) isNR^(d)R^(d). In some embodiments, R^(d) is selected from C₁₋₆ alkyl(e.g., methyl).

In some embodiments, Y is S. In some embodiments, Y is O. In someembodiments, Y is NR^(b). In some embodiments, R^(b) is hydrogen. Insome embodiments, R^(b) is C₁-C₆ alkyl substituted with 0 occurrences ofR^(c) (e.g., methyl, ethyl, isopropyl or sec-butyl). In someembodiments, R^(b) is aralkyl (e.g., benzyl or phenethyl). In someembodiments, R^(b) is C₁₋₆ alkyl substituted with 1 occurrence of R^(c)(e.g., methyl, ethyl or propyl). In some embodiments, R^(c) is C₁₋₆alkoxy (e.g., methoxy). In some embodiments, R^(c) is heterocyclyl(e.g., morpholinyl or piperidinyl). In some embodiments, R^(c) isNR^(d)R^(d). In some embodiments, R^(d) is selected from C₁₋₆ alkyl(e.g., methyl).

In some embodiments, X and Y are both S. In some embodiments, X and Yare both NR^(b). In some embodiments, X and Y are both NCH₃. In someembodiments, one of X and Y is O and the other is S. In someembodiments, one of X and Y is O and the other is NR^(b). In someembodiments, R^(b) is hydrogen. In some embodiments, R^(b) is C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl or sec-butyl).

In some embodiments, one of X and Y is S and the other is NR^(b). Insome embodiments, R^(b) is hydrogen. In some embodiments, R^(b) is C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl or sec-butyl).

In some embodiments, Z is O.

In one aspect, the invention features a method of treating cancercomprising administering to a subject a compound of formula (IV):

wherein:

m is an integer from 0 to 5;

each R¹ is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁₋₆ haloalkoxy, halo, acetyl, —NO₂, aryl, aralkyl,heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl, —C(O)-aralkyl, —C(O)—C₁₋₆alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl, aralkyl and heteroarylgroup is optionally substituted with 0-3 occurrences of R^(c) andwherein two R¹ groups taken together with the carbon atoms to which theyare attached form a heterocyclyl ring;

n is an integer from 0 to 3;

each R² is independently selected from C₁-C₆ alkyl and halo;

B is aryl, monocyclic heteroaryl, cycloalkyl, heterocyclyl, C₁₋₆aralkyl, or C₁₋₆ heteroaralkyl;

L is a linker selected from —SO₂—, —SO₂NR^(a)— and —NR^(a)SO₂—;

each R^(a) is independently selected from hydrogen and C₁-C₆ alkyl;

X and Y are each independently selected from O, S, NR^(b) and CH₂;

Z is O or S;

each R^(b) is independently selected from hydrogen, C₁₋₆ aralkyl, andC₁-C₆ alkyl substituted with 0-1 occurrences of R^(c); and

R^(c) is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, NR^(d)R^(d), and heterocyclyl and wherein two R^(c)groups taken together with the carbon atoms to which they are attachedform a heterocyclyl ring; and

R^(d) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, B is monocyclic aryl (e.g., phenyl). In someembodiments, B is unsubstituted phenyl. In some embodiments, B is phenylsubstituted with 1 R¹. In some embodiments, R¹ is halo (e.g., fluoro,chloro or bromo). In some embodiments, R¹ is C₁-C₆ alkyl (e.g., methylor ethyl). In some embodiments, R¹ is C₁-C₆ alkoxy (e.g., methoxy). Insome embodiments, R¹ is haloalkyl (e.g., trifluoromethyl). In someembodiments, R¹ is acetyl. In some embodiments, R¹ is —NR^(b)-acetyl(e.g., acetamide). In some embodiments, R¹ is —NO₂. In some embodiments,R¹ is —NR^(b)—SO₂-aryl (e.g., —NR^(b)—SO₂-phenyl). In some embodiments,R^(b) is H. In some embodiments, R¹ is —NH—SO₂-phenyl substituted withtwo occurrences of R^(c). In some embodiments, one R^(c) is C₁₋₆ alkoxy(e.g., methoxy) and one R^(c) is halo (e.g., fluoro or chloro). In someembodiments, both R^(c) are halo (e.g., fluoro or chloro). In someembodiments, one R^(c) is C₁₋₆ alkoxy (e.g., methoxy) and one R^(c) isC₁₋₆ alkyl (e.g., methyl).

In some embodiments, B is phenyl substituted with two R¹. In someembodiments, one R¹ is halo (e.g., fluoro or chloro) and the other isC₁-C₆ alkoxy (e.g., methoxy). In some embodiments, both R¹ are halo(e.g., fluoro or chloro). In some embodiments, one R¹ is halo (e.g.,fluoro or chloro) and one R¹ is haloalkyl (e.g., trifluoromethyl). Insome embodiments, one R¹ is halo (e.g., fluoro or chloro) and one R¹ isC₁₋₆ alkyl (e.g., methyl or ethyl). In some embodiments, one R¹ is C₁-C₆alkyl (e.g., methyl) and the other is C₁-C₆ alkoxy (e.g., methoxy). Insome embodiments, both R¹ are C₁-C₆ alkyl (e.g., methyl). In someembodiments, both R¹ are C₁-C₆ alkoxy (e.g., methoxy). In someembodiments, two R¹ groups taken together with the carbon atoms to whichthey are attached form a heterocyclyl ring. In some embodiments, two R¹groups taken together with the carbon atoms to which they are attachedform the following compound:

In some embodiments, two R¹ groups taken together with the carbon atomsto which they are attached form the following compound:

In some embodiments, B is bicyclic aryl (e.g., naphthyl). In someembodiments, B is unsubstituted naphthyl.

In some embodiments, B is monocyclic heteroaryl, e.g., a 5-memberedmonocyclic heteroaryl (e.g., thiophenyl). In some embodiments, B is a6-membered monocyclic heteroaryl, e.g., a 6-membered nitrogen-containingmonocyclic heteroaryl (e.g., pyridyl). In some embodiments, B isunsubstituted pyridyl. In some embodiments, B is pyridyl substitutedwith two R¹. In some embodiments, one R¹ is halo (e.g., chloro) and theother is haloalkyl (e.g., trifluoromethyl).

In some embodiments, B is bicyclic heteroaryl, e.g., a 10-memberedbicyclic heteroaryl (e.g., a 10-membered nitrogen containing bicyclicheteroaryl). In some embodiments, B is a 10-membered nitrogen containingbicyclic heteroaryl (e.g., quinolyl). In some embodiments, B isunsubstituted quinolyl.

In some embodiments, B is a monocyclic heterocyclyl (e.g., a 6-memberedmonocyclic heterocyclyl). In some embodiments, B is a 6-memberednitrogen containing monocyclic heterocyclyl (e.g., piperazinyl). In someembodiments, B is unsubstituted piperazinyl. In some embodiments, B ispiperazinyl substituted with an R¹. In some embodiments, R¹ is —SO₂-aryl(e.g., phenyl or naphthyl). In some embodiments, R¹ is —SO₂-phenylsubstituted with 0 occurrences of R^(c). In some embodiments, R¹ is—SO₂-naphthyl. In some embodiments, R¹ is —SO₂-phenyl substituted with 1occurrence of R^(c). In some embodiments, R^(c) is C₁₋₆ alkoxy (e.g.,methoxy). In some embodiments, R^(c) is halo (e.g., fluoro or chloro).

In some embodiments, R¹ is —SO₂-phenyl substituted with 2 occurrences ofR^(c). In some embodiments, one R^(c) is C₁₋₆ alkoxy (e.g., methoxy) andthe other R^(c) is halo (e.g., chloro or fluoro). In some embodiments,both R^(c) are halo (e.g., fluoro or chloro). In some embodiments, bothR^(c) taken together form a heterocyclyl. In some embodiments, bothR^(c) are taken together to form the compound represented below:

In some embodiments, R¹ is aralkyl (e.g., benzyl).

In some embodiments, R¹ is —C(O)—C₁₋₆ alkoxy (e.g., —C(O)-t-butoxy).

In some embodiments, R¹ is —SO₂-heteroaryl (e.g., —SO₂-pyridyl). In someembodiments, R¹ is —SO₂-pyridyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —SO₂-pyridyl substituted with 1 occurrence ofR^(c). In some embodiments, R^(c) is haloalkyl (e.g., trifluoromethyl).

In some embodiments, R¹ is —C(O)-aralkyl (e.g., —C(O)-benzyl). In someembodiments, R¹ is —C(O)-benzyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —C(O)-benzyl substituted with 1 occurrence ofR^(c). In some embodiments, R^(c) is haloalkyl (e.g., trifluoromethyl).

In some embodiments, B is a monocyclic heterocyclyl (e.g., a 7-memberedmonocyclic heterocyclyl). In some embodiments, B is a 7-memberednitrogen containing monocyclic heterocyclyl (e.g., 1,4-diazepanyl). Insome embodiments, B is unsubstituted 1,4-diazepanyl. In someembodiments, B is 1,4-diazepanyl substituted with an R¹. In someembodiments, R¹ is —SO₂-aryl (e.g., phenyl or naphthyl). In someembodiments, R¹ is —SO₂-phenyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —SO₂-naphthyl. In some embodiments, R¹ is—SO₂-phenyl substituted with 1 occurrence of R^(c). In some embodiments,R^(c) is C₁₋₆ alkoxy (e.g., methoxy). In some embodiments, R^(c) is halo(e.g., fluoro or chloro).

In some embodiments, R¹ is phenyl substituted with 2 occurrences ofR^(c). In some embodiments, one R^(c) is C₁₋₆ alkoxy (e.g., methoxy) andthe other R^(c) is halo (e.g., chloro or fluoro). In some embodiments,both R^(c) are halo (e.g., fluoro or chloro). In some embodiments, bothR^(c) taken together form a heterocyclyl. In some embodiments, bothR^(c) are taken together to form the compound represented below:

In some embodiments, R¹ is aralkyl (e.g., benzyl).

In some embodiments, R¹ is —C(O)—C₁₋₆ alkoxy (e.g., —C(O)-t-butoxy).

In some embodiments, R¹ is —SO₂-heteroaryl (e.g., —SO₂-pyridyl). In someembodiments, R¹ is —SO₂-pyridyl substituted with 0 occurrences of R^(c).In some embodiments, R¹ is —SO₂-pyridyl substituted with 1 occurrence ofR^(c). In some embodiments, R^(c) is haloalkyl (e.g., trifluoromethyl).

In some embodiments, In some embodiments, B is a monocyclic heterocyclyl(e.g., a 6-membered monocyclic heterocyclyl). In some embodiments, B isa 6-membered nitrogen containing monocyclic heterocyclyl (e.g.,piperidinyl). In some embodiments, B is unsubstituted piperidinyl. Insome embodiments, B is piperidinyl substituted with an R¹. In someembodiments, R¹ is —C(O)—NR^(b)-aryl (e.g., —C(O)—NR^(b)-phenyl. In someembodiments, R^(b) is H. In some embodiments, R¹ is —C(O)—NH-phenylsubstituted with two occurrences of R^(c). In some embodiments, bothR^(c) are C₁₋₆ alkyl (e.g., methyl).

In some embodiments, B is cycloalkyl (e.g., cyclohexyl).

In some embodiments, B is C₁₋₆ aralkyl (e.g., benzyl). In someembodiments, B is benzyl substituted with 0 occurrences of R¹.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, R² is C₁-C₆ alkyl (e.g., methyl). In some embodiments, R²is halo (e.g., fluoro, chloro or bromo).

In some embodiments, L is —SO₂NR^(a)—. In some embodiments, R^(a) ishydrogen. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., methyl, ethylor isopropyl). In some embodiments, L is —NR^(a)SO₂—. In someembodiments, R^(a) is hydrogen. In some embodiments, R^(a) is C₁-C₆alkyl (e.g., methyl, ethyl or isopropyl).

In some embodiments, X is S. In some embodiments, X is O. In someembodiments, X is NR^(b). In some embodiments, R^(b) is hydrogen. Insome embodiments, R^(b) is C₁-C₆ alkyl substituted with 0 occurrences ofR^(c) (e.g., methyl, ethyl, isopropyl or sec-butyl). In someembodiments, R^(b) is aralkyl (e.g., benzyl or phenethyl). In someembodiments, R^(b) is C₁₋₆ alkyl substituted with 1 occurrence of R^(c)(e.g., methyl, ethyl or propyl). In some embodiments, R^(c) is C₁₋₆alkoxy (e.g., methoxy). In some embodiments, R^(c) is heterocyclyl(e.g., morpholinyl or piperidinyl). In some embodiments, R^(c) isNR^(d)R^(d). In some embodiments, R^(d) is selected from C₁₋₆ alkyl(e.g., methyl).

In some embodiments, Y is S. In some embodiments, Y is O. In someembodiments, Y is NR^(b). In some embodiments, R^(b) is hydrogen. Insome embodiments, R^(b) is C₁-C₆ alkyl substituted with 0 occurrences ofR^(c) (e.g., methyl, ethyl, isopropyl or sec-butyl). In someembodiments, R^(b) is aralkyl (e.g., benzyl or phenethyl). In someembodiments, R^(b) is C₁₋₆ alkyl substituted with 1 occurrence of R^(c)(e.g., methyl, ethyl or propyl). In some embodiments, R^(c) is C₁₋₆alkoxy (e.g., methoxy). In some embodiments, R^(c) is heterocyclyl(e.g., morpholinyl or piperidinyl). In some embodiments, R^(c) isNR^(d)R^(d). In some embodiments, R^(d) is selected from C₁₋₆ alkyl(e.g., methyl).

In some embodiments, X and Y are both S. In some embodiments, X and Yare both NR^(b). In some embodiments, X and Y are both NCH₃. In someembodiments, one of X and Y is O and the other is S. In someembodiments, one of X and Y is O and the other is NR^(b). In someembodiments, R^(b) is hydrogen. In some embodiments, R^(b) is C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl or sec-butyl).

In some embodiments, one of X and Y is S and the other is NR^(b). Insome embodiments, R^(b) is hydrogen. In some embodiments, R^(b) is C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl or sec-butyl).

In some embodiments, Z is O.

In one aspect, the invention features a method of modulating (e.g.,increasing or decreasing) the level of PKM2 activity and/or glycolysis(e.g., modulating the endogenous ability of a cell in the patient todown regulate PKM2) in a patient in need thereof. The method comprisesthe step of administering an effective amount of a compound describedherein to the patient in need thereof, thereby modulating (e.g.,increasing or decreasing) the level of PKM2 activity and/or glycolysisin the patient. In some embodiments of the invention an activator isused to maintain PKM2 in its active conformation or activate pyruvatekinase activity in proliferating cells as a means to divert glucosemetabolites into catabolic rather than anabolic processes in thepatient.

In another aspect, the invention features a method of regulating cellproliferation in a patient in need thereof. The method comprises thestep of administering an effective amount of a compound described hereinto the patient in need thereof, thereby regulating cell proliferation inthe patient. E.g., this method can modulate growth of a transformedcell, e.g., a cancer cell, or generally modulate growth in aPKM2-dependent cell that undergoes aerobic glycolysis.

In another aspect, the invention features a method of treating a patientsuffering from or susceptible to a disease or disorder associated withthe function of PKM2 in a patient in need thereof. The method comprisesthe step of administering an effective amount of a compound describedherein to the patient in need thereof, thereby treating, preventing orameliorating the disease or disorder in the patient. In anotherembodiment the modulator is provided in a pharmaceutical composition.

In another embodiment the method includes identifying or selecting apatient who would benefit from modulation (e.g., activation orinhibition) of PKM2. E.g., the patient can be identified on the basis ofthe level of PKM2 activity in a cell of the patient (e.g., as opposed tomerely being in need of treatment of the disorder itself, e.g., cancer).In another embodiment the selected patient is a patient suffering fromor susceptible to a disorder or disease identified herein, e.g., adisorder characterized by unwanted cell growth or proliferation, e.g.,cancer, obesity, diabetes, atherosclerosis, restenosis, and autoimmunediseases.

In another embodiment the compound described herein is administered at adosage and frequency sufficient to increase lactate production oroxidative phosphorylation.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁-C₁₂ alkyl indicates that the group may have from1 to 12 (inclusive) carbon atoms in it. The term “haloalkyl” refers toan alkyl in which one or more hydrogen atoms are replaced by halo, andincludes alkyl moieties in which all hydrogens have been replaced byhalo (e.g., perfluoroalkyl). The terms “arylalkyl” or “aralkyl” refer toan alkyl moiety in which an alkyl hydrogen atom is replaced by an arylgroup. Aralkyl includes groups in which more than one hydrogen atom hasbeen replaced by an aryl group. Examples of “arylalkyl” or “aralkyl”include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl,and trityl groups.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,and —CH₂CH₂CH₂—.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and having one or more double bonds.Examples of alkenyl groups include, but are not limited to, allyl,propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doublebond carbons may optionally be the point of attachment of the alkenylsubstituent. The term “alkynyl” refers to a straight or branchedhydrocarbon chain containing 2-12 carbon atoms and characterized inhaving one or more triple bonds. Examples of alkynyl groups include, butare not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triplebond carbons may optionally be the point of attachment of the alkynylsubstituent.

The terms “alkylamino” and “dialkylamino” refer to —NH(alkyl) and—NH(alkyl)₂ radicals respectively. The term “aralkylamino” refers to a—NH(aralkyl) radical. The term alkylaminoalkyl refers to a(alkyl)NH-alkyl-radical; the term dialkylaminoalkyl refers to a(alkyl)₂N-alkyl-radical The term “alkoxy” refers to an —O-alkyl radical.The term “mercapto” refers to an SH radical. The term “thioalkoxy”refers to an —S-alkyl radical. The term thioaryloxy refers to an —S-arylradical.

The terms “arylalkyl” or “aralkyl” refer to an alkyl moiety in which analkyl hydrogen atom is replaced by an aryl group. Aralkyl includesgroups in which more than one hydrogen atom has been replaced by an arylgroup. Examples of “arylalkyl” or “aralkyl” include benzyl,2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and tritylgroups.

The term “aryl” refers to an aromatic monocyclic, bicyclic, or tricyclichydrocarbon ring system, wherein any ring atom capable of substitutioncan be substituted (e.g., by one or more substituents). Examples of arylmoieties include, but are not limited to, phenyl, naphthyl, andanthracenyl.

The term “cycloalkyl” as employed herein includes saturated cyclic,bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12carbons. Any ring atom can be substituted (e.g., by one or moresubstituents). The cycloalkyl groups can contain fused rings. Fusedrings are rings that share a common carbon atom. Examples of cycloalkylmoieties include, but are not limited to, cyclopropyl, cyclohexyl,methylcyclohexyl, adamantyl, and norbornyl.

The term “heterocyclyl” refers to a nonaromatic 3-10 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms ofN, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Theheteroatom may optionally be the point of attachment of the heterocyclylsubstituent. Any ring atom can be substituted (e.g., by one or moresubstituents). The heterocyclyl groups can contain fused rings. Fusedrings are rings that share a common carbon atom. Examples ofheterocyclyl include, but are not limited to, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl,quinolinyl, and pyrrolidinyl.

The term “cycloalkenyl” refers to partially unsaturated, nonaromatic,cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 5to 12 carbons, preferably 5 to 8 carbons. The unsaturated carbon mayoptionally be the point of attachment of the cycloalkenyl substituent.Any ring atom can be substituted (e.g., by one or more substituents).The cycloalkenyl groups can contain fused rings. Fused rings are ringsthat share a common carbon atom. Examples of cycloalkenyl moietiesinclude, but are not limited to, cyclohexenyl, cyclohexadienyl, ornorbornenyl.

The term “heterocycloalkenyl” refers to a partially saturated,nonaromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6,or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively). The unsaturated carbon or the heteroatom may optionallybe the point of attachment of the heterocycloalkenyl substituent. Anyring atom can be substituted (e.g., by one or more substituents). Theheterocycloalkenyl groups can contain fused rings. Fused rings are ringsthat share a common carbon atom. Examples of heterocycloalkenyl includebut are not limited to tetrahydropyridyl and dihydropyranyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively). Any ring atom can besubstituted (e.g., by one or more substituents).

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group.

The term “oxo” refers to an oxygen atom, which forms a carbonyl whenattached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent,any of which may be further substituted (e.g., by one or moresubstituents).

The term “substituents” refers to a group “substituted” on an alkyl,cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Anyatom can be substituted. Suitable substituents include, withoutlimitation, alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11,C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g.,perfluoroalkyl such as CF₃), aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl,alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF₃), halo, hydroxy,carboxy, carboxylate, cyano, nitro, amino, alkyl amino, SO₃H, sulfate,phosphate, methylenedioxy (—O—CH₂—O— wherein oxygens are attached tovicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C═S), imino (alkyl,aryl, aralkyl), S(O)_(n)alkyl (where n is 0-2), S(O)_(n) aryl (where nis 0-2), S(O)_(n) heteroaryl (where n is 0-2), S(O)_(n) heterocyclyl(where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester(alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-, di-,alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinationsthereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, andcombinations thereof). In one aspect, the substituents on a group areindependently any one single, or any subset of the aforementionedsubstituents. In another aspect, a substituent may itself be substitutedwith any one of the above substituents.

The term “selective” is meant at least 2-fold, 3-fold, 4-fold, 5-fold,6-fold, or 10-fold greater modulation (e.g., inhibition) of M2 than M1.

The term “activator” as used herein means an agent that (measurably)increases the activity of a pyruvate kinase (e.g., PKM2) or causespyruvate kinase (e.g., PKM2) activity to increase to a level that isgreater than PKM2's basal levels of activity. For example, the activatormay mimic the effect caused by a natural ligand (e.g., FBP). Theactivator effect caused by the agent may be to the same, or to agreater, or to a lesser extent than the activating effect caused by anatural ligand, but the same type of effect is caused. Peptides, nucleicacids, and small molecules may be activators. An agent can be evaluatedto determine if it is an activator by measuring either directly orindirectly the activity of the pyruvate kinase when subjected to theagent. The activity of the agent can be measured, for example, against acontrol substance. In some instances, the activity measured of the agentis for activation of PKM2. The activity of PKM2 can be measured, forexample, by monitoring the concentration of a substrate such as ATP orNADH.

The term “inhibitor” as used herein means an agent that measurablyslows, stops, decreases or inactivates the enzymatic activity ofpyruvate kinase (e.g., PKM2) to decrease to a level that is less thanthe pyruvate kinase's (e.g., PKM2's) basal levels of activity.Inhibitors of pyruvate kinase (e.g., PKM2) may be peptides or nucleicacids. An agent can be evaluated to determine if it is an inhibitor bymeasuring either directly or indirectly the activity of the pyruvatekinase when subjected to the agent. The activity of the agent can bemeasured, for example, against a control substance. In some instances,the activity measured of the agent is for inhibition of PKM2. Theactivity of PKM2 can be measured, for example, by monitoring theconcentration of a substrate such as ATP or NADH.

DETAILED DESCRIPTION

This invention is not limited in its application to the details ofconstruction and the arrangement of components set forth in thefollowing description or illustrated in the drawings. The invention iscapable of other embodiments and of being practiced or of being carriedout in various ways. Also, the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing”, “involving”, and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

Compounds

Described herein are compounds and compositions that modulate PKM2, forexample, activate or inhibit PKM2. Compounds that modulate PKM2, e.g.,activate or inhibit PKM2, can be used to treat disorders such asneoplastic disorders (e.g., cancer) or fat related disorders (e.g.,obesity). Exemplary compounds include the compounds of Formula I,Formula II, Formula III, Formula IV and Formula V described herein. Insome embodiments, a compound described herein modulates PKM2 byinteracting (e.g., binding) with the FBP binding pocket. For example, acompound described herein can compete with FBP binding in PKM2.

In some embodiments a compound described herein has one or moreproperties described herein, e.g., one or more of the followingproperties: it is an allosteric modulator (e.g., inhibitor oractivator); it modulates the release of FBP (e.g., inhibits orpromotes); it is a modulator (e.g., agonist or antagonist) of FBP, e.g.,an agonist which binds with a lower, about the same, or higher affinitythan does FBP; it modulates (e.g., inhibits or promotes) the dissolutionof tetrameric PKM2; it modulates (e.g., promotes or inhibits) theassembly of tetrameric PKM2; it selectively modulates (e.g., inhibits oractivates) PKM2 over at least one other isoform of PK, e.g., it isselective for PKM2 over PKR, PKM1, or PKL; is has an affinity for PKM2which is greater than its affinity for at least one other isoform of PK,e.g., PKR, PKM1, or PKL.

In another embodiment the activator of PKM2 utilized in the methods andcompositions of this invention operates by or has one or more of thefollowing mechanisms or properties:

-   -   a. it is an allosteric activator of PKM2;    -   b. it modulates (e.g., stabilizes or inhibits) the binding of        FBP in a binding pocket of PKM2;    -   c. it modulates (e.g., inhibits or promotes) the release of FBP        from a binding pocket of PKM2;    -   d. it is a modulator (e.g., an agonist or antagonist), e.g., an        analog, of FBP, e.g., an agonist which binds PKM2 with a lower,        about the same, or higher affinity than does FBP;    -   e. it modulates (e.g., inhibits or promotes) the dissolution of        tetrameric PKM2;    -   f. it modulates (e.g., inhibits or promotes) the assembly of        tetrameric PKM2;    -   g. it modulates (e.g., stabilizes or inhibits) the tetrameric        conformation of PKM2;    -   h. it modulates (e.g., inhibits or promotes) the binding of a        phosphotyrosine containing polypeptide to PKM2;    -   i. it modulates (e.g., inhibits or promotes) the ability of a        phosphotyrosine containing polypeptide to induce release of FBP        from PKM2, e.g., by inducing a change in the conformation of        PKM2, e.g., in the position of Lys 433, thereby hindering the        release of FBP;    -   k. it binds to or changes the position of Lys 433 relative to        the FBP binding pocket;    -   l. it selectively modulates (e.g., activates or inhibits) PKM2        over at least one other isoform of PK, e.g., it is selective for        PKM2 over one or more of PKR, PKM1, or PKL;    -   m. it has an affinity for PKM2 which is greater than its        affinity for at least one other isoform of PK, e.g., PKR, PKM1,        or PKL.

A compound described herein may be an activator of PKM2. Exemplarycompounds are shown in Table 1. As shown in Table 1, A refers to anactivator of PKM2 with an AC₅₀<1 μM. B refers to an activator of PKM2with an AC₅₀ between 1 μM and 10 μM. C refers to an activator of PKM2with an AC₅₀ between 10 μM and 50 μM. C refers to an activator of PKM2with an AC₅₀ between 50 μM and 100 μM. D refers to an activator of PKM2with an AC₅₀>100 μM. E refers to an activator of PKM2 that has not beentested.

TABLE 1 Structure AC₅₀

E

C

B

C

C

D

E

E

B

B

B

D

B

E

B

C

B

E

B

B

B

E

B

C

A

C

B

D

B

C

A

A

B

E

B

D

B

C

A

C

A

B

A

D

D

C

B

E

B

C

C

C

C

C

B

C

D

C

A

C

A

D

B

E

B

B

C

B

E

E

B

C

B

E

E

C

C

E

C

D

A

E

B

E

B

C

C

E

C

B

B

C

C

C

B

C

B

E

E

B

B

B

C

E

E

E

E

C

E

B

E

B

E

C

E

E

C

B

E

C

E

E

E

E

E

C

E

C

E

B

C

C

E

E

E

A

A

B

B

A

B

A

B

B

A

E

B

A

B

B

A

A

A

B

E

B

E

B

B

B

E

B

E

E

D

C

A

B

B

B

B

B

B

B

B

A

A

B

B

B

B

A

B

B

B

B

D

C

A

E

A

A

A

A

A

B

A

A

B

B

A

A

A

B

B

E

B

B

B

C

A

B

A

A

A

A

A

A

A

A

A

B

A

B

B

D

B

B

D

B

A

B

A

A

A

D

B

A

B

A

A

B

A

D

A

A

B

B

B

A

B

A

B

D

B

The compounds described herein can be made using a variety of synthetictechniques. In some embodiments, a compound described herein may beavailable from a commercial source. Schemes 1 and 2 below depictrepresentative syntheses of certain compounds described herein. Scheme 3represents the synthesis of a compound described herein.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Additionally, the various synthetic steps maybe performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this invention may contain one or more asymmetriccenters and thus occur as racemates and racemic mixtures, singleenantiomers, individual diastereomers and diastereomeric mixtures. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. The compounds of this invention may also containlinkages (e.g., carbon-carbon bonds) or substituents that can restrictbond rotation, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded in the present invention.

The compounds of this invention may also be represented in multipletautomeric forms, in such instances, the invention expressly includesall tautomeric forms of the compounds described herein, even though onlya single tautomeric form may be represented (e.g., alkylation of a ringsystem may result in alkylation at multiple sites, the inventionexpressly includes all such reaction products). All such isomeric formsof such compounds are expressly included in the present invention. Allcrystal forms of the compounds described herein are expressly includedin the present invention.

The compounds of this invention include the compounds themselves, aswell as their salts and their prodrugs, if applicable. A salt, forexample, can be formed between an anion and a positively chargedsubstituent (e.g., amino) on a compound described herein. Suitableanions include chloride, bromide, iodide, sulfate, nitrate, phosphate,citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, asalt can also be formed between a cation and a negatively chargedsubstituent (e.g., carboxylate) on a compound described herein. Suitablecations include sodium ion, potassium ion, magnesium ion, calcium ion,and an ammonium cation such as tetramethylammonium ion. Examples ofprodrugs include esters and other pharmaceutically acceptablederivatives, which, upon administration to a subject, are capable ofproviding active compounds.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selected biological properties, e.g.,targeting to a particular tissue. Such modifications are known in theart and include those which increase biological penetration into a givenbiological compartment (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

In an alternate embodiment, the compounds described herein may be usedas platforms or scaffolds that may be utilized in combinatorialchemistry techniques for preparation of derivatives and/or chemicallibraries of compounds. Such derivatives and libraries of compounds havebiological activity and are useful for identifying and designingcompounds possessing a particular activity. Combinatorial techniquessuitable for utilizing the compounds described herein are known in theart as exemplified by Obrecht, D. and Villalgrodo, J. M.,Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries, Pergamon-Elsevier ScienceLimited (1998), and include those such as the “split and pool” or“parallel” synthesis techniques, solid-phase and solution-phasetechniques, and encoding techniques (see, for example, Czarnik, A. W.,Curr. Opin. Chem. Bio., (1997) 1, 60. Thus, one embodiment relates to amethod of using the compounds described herein for generatingderivatives or chemical libraries comprising: 1) providing a bodycomprising a plurality of wells; 2) providing one or more compoundsidentified by methods described herein in each well; 3) providing anadditional one or more chemicals in each well; 4) isolating theresulting one or more products from each well. An alternate embodimentrelates to a method of using the compounds described herein forgenerating derivatives or chemical libraries comprising: 1) providingone or more compounds described herein attached to a solid support; 2)treating the one or more compounds identified by methods describedherein attached to a solid support with one or more additionalchemicals; 3) isolating the resulting one or more products from thesolid support. In the methods described above, “tags” or identifier orlabeling moieties may be attached to and/or detached from the compoundsdescribed herein or their derivatives, to facilitate tracking,identification or isolation of the desired products or theirintermediates. Such moieties are known in the art. The chemicals used inthe aforementioned methods may include, for example, solvents, reagents,catalysts, protecting group and deprotecting group reagents and thelike. Examples of such chemicals are those that appear in the varioussynthetic and protecting group chemistry texts and treatises referencedherein.

Methods of Evaluating Compounds

The compounds described herein can be evaluated for ability to modulatePKM2 (e.g., activate or inhibit PKM2) by methods known in the art.Exemplary methods include contacting the compound with a cell-basedassay which allows assessment of the ability to modulate (e.g., activateor inhibit) PKM2. E.g., the candidate compound can be contacted with acell and measuring the consumption of oxygen or production of lactate. Achange in cellular phosphoenolpyruvate, a change in glycerol-phosphate,a change in ribose or deoxyribose, a change in lipid synthesis, or achange in glucose conversion to lipid or nucleic acids or amino acids orprotein can also be used to evaluate a compound for its ability tomodulate PKM2 (e.g., activate or inhibit PKM2). The evaluation couldalso include measuring a change in pyruvate or a determination of analteration in mitochondrial membrane potential, e.g., as measured byfluorescent potentiometric dyes.

PKM1 and PKM2 for use in the screening method may be produced by anymethod known in the art for expression of recombinant proteins. Forexample, nucleic acids that encode the desired polypeptide may beintroduced into various cell types or cell-free systems for expression.Eukaryotic (e.g., COS, HEK293T, CHO, and NIH cell lines) and prokaryotic(e.g., E. coli) expression systems may be generated in which a PKMsequence is introduced into a plasmid or other vector, which is thenused to transform living cells. Constructs in which the PKM cDNAcontains the entire open reading frame, or biologically active fragmentthereof, are inserted in the correct orientation into an expressionplasmid and may be used for protein expression. Prokaryotic andeukaryotic expression systems allow for the expression and recovery offusion proteins in which the PKM protein is covalently linked to a tagmolecule on either the amino terminal or carboxy terminal side, whichfacilitates identification and/or purification. Examples of tags thatcan be used include hexahistidine, HA, FLAG, and c-myc epitope tags. Anenzymatic or chemical cleavage site can be engineered between the PKMprotein and the tag molecule so that the tag can be removed followingpurification.

The activity of the PKM enzyme measured in the screening assay may bemeasured by, e.g., monitoring the concentration of a substrate (e.g.,ATP or NADH) present in the reaction mixture. Pyruvate, produced by theenzymatic activity of pyruvate kinase, is converted into lactate bylactate dehydrogenase, which requires the consumption of NADH(NADH→NAD+). Thus, the activity of PKM2 can be indirectly measured bymonitoring the consumption of NADH through, e.g., fluorescence assays.Additionally, the activity of the PKM2 enzyme can be directly monitoredby measuring the production of ATP, as ATP is produced whenphosphoenolpyruvate is converted to pyruvate. Methods for monitoring theamount of substrate in a reaction mixture include, e.g., absorbance,fluorescence, Raman scattering, phosphorescence, luminescence,luciferase assays, and radioactivity.

The screening procedure requires the presence of specific components inthe reaction mixture. Components utilized in the assay include, e.g., anucleoside diphosphate (e.g., ADP), phosphoenolpyruvate, NADH, lactatedehydrogenase, FBP, a reducing agent (e.g., dithiothreitol), a detergent(e.g., Brij 35), glycerol, and a solvent (e.g., DMSO). Exemplaryreaction conditions are found in Table 2.

TABLE 2 Amount in In- Amount in Ac- Component of Reaction Conditionhibition Assay tivation Assay ADP 0.1-5.0 mM 0.1-5.0 mMPhosphoenolpyruvate 0.1-5.0 mM 0.1-5.0 mM NADH 10-1000 μM 10-1000 μMLactate dehydrogenase 0.1-10 units 0.1-10 unitsFructose-1,6-bisphosphate 1-500 μM 0 DTT 0.1-50 mM 0.1-50 mM Brij 350.01-1% 0.01-1% Glycerol 0.1-10% 0.1-10% Pyruvate Kinase M2 (used forscreen) 1-100 pg 1-100 pg DMSO   1-10%   1-10%

Candidate inhibitory compounds are chosen if they demonstratespecificity for PKM2 and inhibition of the PKM2 enzyme greater than 10,15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99,or 99.9%.

Candidate activator compounds are chosen if they demonstrate specificityand activation of PKM2 enzyme in the absence of FBP to a level greaterthan that of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 99, or 100% in the presence of FBP. Furthermore, specificcandidate activators of PKM2 can be evaluated in the presence or absenceof a phosphotyrosine peptide. Phosphotyrosine peptide binding to PKM2leads to a dissociation of FBP from PKM2 and conformational changes ofPKM2 from an active, tetrameric form to an inactive form. Compounds thatbind to PKM2 and lock the enzyme in the active confirmation even in thepresence of a phosphotyrosine peptide will lead to the loss ofallosteric control of PKM2 needed for shunting the biochemicalintermediates from glycolysis into biosynthesis of other intermediates.This, in turn, will lead to inhibition of growth of cancer cells,activated immune cells and fat cells.

Methods of Treatment

The compounds and compositions described herein can be administered tocells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., invivo, to treat, prevent, and/or diagnose a variety of disorders,including those described herein below.

As used herein, the term “treat” or “treatment” is defined as theapplication or administration of a compound, alone or in combinationwith, a second compound to a subject, e.g., a patient, or application oradministration of the compound to an isolated tissue or cell, e.g., cellline, from a subject, e.g., a patient, who has a disorder (e.g., adisorder as described herein), a symptom of a disorder, or apredisposition toward a disorder, with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisorder, one or more symptoms of the disorder or the predispositiontoward the disorder (e.g., to prevent at least one symptom of thedisorder or to delay onset of at least one symptom of the disorder).

As used herein, an amount of a compound effective to treat a disorder,or a “therapeutically effective amount” refers to an amount of thecompound which is effective, upon single or multiple dose administrationto a subject, in treating a cell, or in curing, alleviating, relievingor improving a subject with a disorder beyond that expected in theabsence of such treatment.

As used herein, an amount of a compound effective to prevent a disorder,or “a prophylactically effective amount” of the compound refers to anamount effective, upon single- or multiple-dose administration to thesubject, in preventing or delaying the occurrence of the onset orrecurrence of a disorder or a symptom of the disorder.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patienthaving a disorder, e.g., a disorder described herein or a normalsubject. The term “non-human animals” of the invention includes allvertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles)and mammals, such as non-human primates, domesticated and/oragriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

Neoplastic Disorders

A compound or composition described herein can be used to treat aneoplastic disorder. A “neoplastic disorder” is a disease or disordercharacterized by cells that have the capacity for autonomous growth orreplication, e.g., an abnormal state or condition characterized byproliferative cell growth. Exemplary neoplastic disorders include:carcinoma, sarcoma, metastatic disorders (e.g., tumors arising fromprostate, colon, lung, breast and liver origin), hematopoieticneoplastic disorders, e.g., leukemias, metastatic tumors. Prevalentcancers include: breast, prostate, colon, lung, liver, and pancreaticcancers. Treatment with the compound may be in an amount effective toameliorate at least one symptom of the neoplastic disorder, e.g.,reduced cell proliferation, reduced tumor mass, etc.

The disclosed methods are useful in the prevention and treatment ofcancer, including for example, solid tumors, soft tissue tumors, andmetastases thereof. The disclosed methods are also useful in treatingnon-solid cancers. Exemplary solid tumors include malignancies (e.g.,sarcomas, adenocarcinomas, and carcinomas) of the various organ systems,such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon),and genitourinary (e.g., renal, urothelial, or testicular tumors)tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas includecolorectal cancers, renal-cell carcinoma, liver cancer, non-small cellcarcinoma of the lung, and cancer of the small intestine.

Exemplary cancers described by the national cancer institute include:Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia,Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma;Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-RelatedMalignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar;Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; BladderCancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/MalignantFibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult;Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, CerebellarAstrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/MalignantGlioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor,Medulloblastoma, Childhood; Brain Tumor, Supratentorial PrimitiveNeuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway andHypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); BreastCancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; BreastCancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor,Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical;Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central NervousSystem Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; CerebralAstrocytoma/Malignant Glioma, Childhood; Cervical Cancer; ChildhoodCancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia;Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of TendonSheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CellLymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer,Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Familyof Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal GermCell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, IntraocularMelanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric(Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; GastrointestinalCarcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ CellTumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational TrophoblasticTumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathwayand Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer;Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver)Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin'sLymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; HypopharyngealCancer; Hypothalamic and Visual Pathway Glioma, Childhood; IntraocularMelanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma;Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia,Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood;Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia,Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary);Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; LungCancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; LymphoblasticLeukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma,AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma,Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma,Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma,Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central NervousSystem; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; MalignantMesothelioma, Adult; Malignant Mesothelioma, Childhood; MalignantThymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular;Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous NeckCancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome,Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides;Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer;Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma;Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood;Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer;Oral Cancer, Childhood; Oral Cavity and Lip Cancer; OropharyngealCancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; OvarianCancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor;Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; PancreaticCancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus andNasal Cavity Cancer; Parathyroid Cancer; Penile Cancer;Pheochromocytoma; Pineal and Supratentorial Primitive NeuroectodermalTumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult;Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; RenalCell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis andUreter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma,Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, SoftTissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood;Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell LungCancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft TissueSarcoma, Childhood; Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer,Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood;T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood;Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Cancer of, Childhood; UnusualCancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer;Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway andHypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor. Metastases of the aforementioned cancerscan also be treated or prevented in accordance with the methodsdescribed herein.

Cancer Combination Therapies

In some embodiments, a compound described herein is administeredtogether with an additional cancer treatment. Exemplary cancertreatments include, for example: chemotherapy, targeted therapies suchas antibody therapies, immunotherapy, and hormonal therapy. Examples ofeach of these treatments are provided below.

Chemotherapy

In some embodiments, a compound described herein is administered with achemotherapy. Chemotherapy is the treatment of cancer with drugs thatcan destroy cancer cells. “Chemotherapy” usually refers to cytotoxicdrugs which affect rapidly dividing cells in general, in contrast withtargeted therapy. Chemotherapy drugs interfere with cell division invarious possible ways, e.g., with the duplication of DNA or theseparation of newly formed chromosomes. Most forms of chemotherapytarget all rapidly dividing cells and are not specific for cancer cells,although some degree of specificity may come from the inability of manycancer cells to repair DNA damage, while normal cells generally can.

Examples of chemotherapeutic agents used in cancer therapy include, forexample, antimetabolites (e.g., folic acid, purine, and pyrimidinederivatives) and alkylating agents (e.g., nitrogen mustards,nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes,aziridines, spindle poison, cytotoxic agents, toposimerase inhibitorsand others). Exemplary agents include Aclarubicin, Actinomycin,Alitretinon, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,Belotecan, Bexarotene, endamustine, Bleomycin, Bortezomib, Busulfan,Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur,Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin,Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine,Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine,Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin,Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide,Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide,Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomaldoxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone,Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate,Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin,Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel,Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin,Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide,Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine,Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and othercytostatic or cytotoxic agents described herein.

Because some drugs work better together than alone, two or more drugsare often given at the same time. Often, two or more chemotherapy agentsare used as combination chemotherapy. In some embodiments, thechemotherapy agents (including combination chemotherapy) can be used incombination with a compound described herein.

Targeted Therapy

In some embodiments, a compound described herein is administered with atargeted therapy. Targeted therapy constitutes the use of agentsspecific for the deregulated proteins of cancer cells. Small moleculetargeted therapy drugs are generally inhibitors of enzymatic domains onmutated, overexpressed, or otherwise critical proteins within the cancercell. Prominent examples are the tyrosine kinase inhibitors such asAxitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib,gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib,Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitorssuch as Alvocidib and Seliciclib. Monoclonal antibody therapy is anotherstrategy in which the therapeutic agent is an antibody whichspecifically binds to a protein on the surface of the cancer cells.Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®)typically used in breast cancer, and the anti-CD20 antibody rituximaband Tositumomab typically used in a variety of B-cell malignancies.Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab,Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusionproteins include Aflibercept and Denileukin diftitox. In someembodiments, the targeted therapy can be used in combination with acompound described herein.

Targeted therapy can also involve small peptides as “homing devices”which can bind to cell surface receptors or affected extracellularmatrix surrounding the tumor. Radionuclides which are attached to thesepeptides (e.g., RGDs) eventually kill the cancer cell if the nuclidedecays in the vicinity of the cell. An example of such therapy includesBEXXAR®.

Immunotherapy

In some embodiments, a compound described herein is administered with animmunotherapy. Cancer immunotherapy refers to a diverse set oftherapeutic strategies designed to induce the patient's own immunesystem to fight the tumor. Contemporary methods for generating an immuneresponse against tumors include intravesicular BCG immunotherapy forsuperficial bladder cancer, and use of interferons and other cytokinesto induce an immune response in renal cell carcinoma and melanomapatients.

Allogeneic hematopoietic stem cell transplantation can be considered aform of immunotherapy, since the donor's immune cells will often attackthe tumor in a graft-versus-tumor effect. In some embodiments, theimmunotherapy agents can be used in combination with a compounddescribed herein.

Hormonal Therapy

In some embodiments, a compound described herein is administered with ahormonal therapy. The growth of some cancers can be inhibited byproviding or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostatecancers. Removing or blocking estrogen or testosterone is often animportant additional treatment. In certain cancers, administration ofhormone agonists, such as progestogens may be therapeuticallybeneficial. In some embodiments, the hormonal therapy agents can be usedin combination with a compound described herein.

Obesity and Fat Disorders

A compound or composition described herein can be used to treat orprevent obesity, e.g., in a human subject, e.g. a child or adultsubject. “Obesity” refers to a condition in which a subject has a bodymass index of greater than or equal to 30. Many compounds describedherein can be used to treat or prevent an over-weight condition.“Over-weight” refers to a condition in which a subject has a body massindex of greater or equal to 25.0. The body mass index (BMI) and otherdefinitions are according to the “NIH Clinical Guidelines on theIdentification and Evaluation, and Treatment of Overweight and Obesityin Adults” (1998). Treatment with the compound may be in an amounteffective to alter the weight of the subject, e.g., by at least 2, 5, 7,10, 12, 15, 20, 25, 30, 25, 40, 45, 50, or 55%. Treatment with acompound may be in an amount effective to reduce the body mass index ofthe subject, e.g., to less than 30, 28, 27, 25, 22, 20, or 18. Thecompounds can be used to treat or prevent aberrant or inappropriateweight gain, metabolic rate, or fat deposition, e.g., anorexia, bulimia,obesity, diabetes, or hyperlipidemia (e.g., elevated triglyceridesand/or elevated cholesterol), as well as disorders of fat or lipidmetabolism.

A compound or composition described herein can be administered to treatobesity associated with Prader-Willi Syndrome (PWS). PWS is a geneticdisorder associated with obesity (e.g., morbid obesity).

A compound or composition described herein can be used to reduce bodyfat, prevent increased body fat, reduce cholesterol (e.g., totalcholesterol and/or ratios of total cholesterol to HDL cholesterol),and/or reduce appetite in individuals having PWS associated obesity,and/or reduce comorbidities such as diabetes, cardiovascular disease,and stroke.

Compositions and Routes of Administration

The compositions delineated herein include the compounds delineatedherein (e.g., a compound described herein), as well as additionaltherapeutic agents if present, in amounts effective for achieving amodulation of disease or disease symptoms, including those describedherein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agentswhich are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is useful when the desired treatment involves areas or organsreadily accessible by topical application. For application topically tothe skin, the pharmaceutical composition should be formulated with asuitable ointment containing the active components suspended ordissolved in a carrier. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions of this invention may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparationscontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Patient Selection and Monitoring

The compounds described herein can modulate PKM2. Accordingly, a patientand/or subject can be selected for treatment using a compound describedherein by first evaluating the patient and/or subject to determinewhether the subject is in need of modulation of PKM2, and if the subjectis determined to be in need of modulation of PKM2, then optionallyadministering to the subject a compound described herein.

A subject can be evaluated as being in need of modulation of PKM2 usingmethods known in the art, e.g., by measuring the presence and/oractivity of PKM2 in the patient. In some embodiments, the activityand/or level of PKM2 is evaluated in the cancer.

A patient receiving a compound described herein can be monitored, forexample, for improvement in the condition and/or adverse effects.Improvement of a patient's condition can be evaluated, for example, bymonitoring the growth, absence of growth, or regression of the cancer(e.g., a tumor). In some embodiments, the patient is evaluated using aradiological assay or evaluation of hemolytic parameters.

EXAMPLES Example 1 PKM2 Assay

Procedure:

-   -   PKM2 stock enzyme solution was diluted in Reaction Buffer    -   2 μL of compound was added into each well first, and then 180 μL        of the Reaction Mix was added.    -   Reaction mixture with compound (without ADP) were incubated for        30 minutes at 4° C.    -   Plates were re-equilibrated to room temperature prior to adding        20 μL ADP to initiate the reaction.    -   Reaction progress was measured as changes in absorbance at 340        nm wavelength at room temperature (25° C.)        Reaction Mix: PKM2 (50 ng/well), ADP (0.7 mM), PEP (0.15 mM),        NADH (180 μM), LDH (2 units) in Reaction Buffer        Reaction Buffer: 100 mM KCl, 50 mM Tris pH 7.5, 5 mM MgCl2, 1 mM        DTT, 0.03% BSA.        Results from this assay can be seen in Table 1.

Having thus described several aspects of at least one embodiment of thisinvention, it is to be appreciated various alterations, modifications,and improvements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure, and are intended to be within the spirit and scope ofthe invention. Accordingly, the foregoing description and drawings areby way of example only.

The invention claimed is:
 1. A compound selected from formula (I):

wherein: m is an integer from 0 to 5; each R¹ is independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁₋₆ haloalkoxy, halo,acetyl, —NO₂, aryl, aralkyl, heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl,—C(O)-aralkyl, —C(O)—C₁₋₆ alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl,aralkyl and heteroaryl group is optionally substituted with 0-3occurrences of R^(c) and wherein two R¹ groups taken together with thecarbon atoms to which they are attached form a heterocyclyl ring; n isan integer from 1 to 3; each R² is independently selected from C₁-C₆alkyl and halo; B is aryl; L is a linker selected from —SO₂—,—SO₂NR^(a)— and —NR^(a)SO₂—; each R^(a) is independently selected fromhydrogen and C₁-C₆ alkyl; wherein one of X and Y is O and the other isNR^(b) or one of X and Y is S and the other is NR^(b); Z is O or S; eachR^(b) is C₁-C₆ alkyl substituted with 0-1 occurrences of R^(c); andR^(c) is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, NR^(d)R^(d), and heterocyclyl and wherein two R^(c)groups taken together with the carbon atoms to which they are attachedform a heterocyclyl ring; and R^(d) is independently selected from H andC₁₋₆ alkyl.
 2. The compound of claim 1, wherein B is substituted withone R¹.
 3. The compound of claim 1, wherein B is a monocyclic aryl. 4.The compound of claim 3, wherein B is substituted with one or two R¹. 5.The compound of claim 1, wherein n is
 1. 6. The compound of claim 5,wherein the compound of formula (I) is represented by the followingformula:


7. The compound of claim 1, wherein L is —SO—NR^(a)—.
 8. The compound ofclaim 7, wherein R^(a) is H.
 9. The compound of claim 1, wherein L is—SO₂—.
 10. The compound of claim 1, wherein each R¹ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, halo, acetyl and—NO₂.
 11. The compound of claim 1, wherein Z is O.
 12. The compound ofclaim 1, wherein one of X and Y is O and the other is NR^(b).
 13. Thecompound of claim 1, wherein one of X and Y is S and the other isNR^(b).
 14. A compound selected from formula (III):

wherein: m is an integer from 0 to 5; each R¹ is independently selectedfrom C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁₋₆ haloalkoxy, halo,acetyl, —NO₂, aryl, aralkyl, heteroaryl, —SO₂-aryl, —C(O)—NR^(b)-aryl,—C(O)-aralkyl, —C(O)—C₁₋₆ alkoxy, —NR^(b)—SO₂-aryl, wherein each aryl,aralkyl and heteroaryl group is optionally substituted with 0-3occurrences of R^(c) and wherein two R¹ groups taken together with thecarbon atoms to which they are attached form a heterocyclyl ring; eachR² is independently selected from C₁-C₆ alkyl and halo; each R^(b) isindependently selected from hydrogen, C₁₋₆ aralkyl, and C₁-C₆ alkylsubstituted with 0-1 occurrences of R^(c); R^(c) is independentlyselected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, halo,NR^(d)R^(d), and heterocyclyl and wherein two R^(c) groups takentogether with the carbon atoms to which they are attached form aheterocyclyl ring; and R^(d) is independently selected from H and C₁₋₆alkyl.
 15. The compound of claim 14, wherein m is
 0. 16. The compound ofclaim 14, wherein m is 1 or
 2. 17. The compound of claim 14, whereineach R¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, halo, acetyl and —NO₂.
 18. The compound of claim 14, whereinR² is methyl.